To date, a variety of beta-lactam drugs have been developed and beta-lactam drugs have become clinically extremely important antimicrobial drugs. However, there are increasing number of bacterial types which have obtained resistancy against beta-lactam drugs by producing beta-lactamase, which degrade beta-lactam drugs.
According to the Ambler molecular classification, beta-lactamase are largely classified into four classes. Specifically, those are Class A (TEM type, SHV type, CTX-M type and the like), Class B (IMP type, VIM type, L-1 type and the like), Class C (AmpC type) and Class D (OXA type and the like). Amongst these, Classes A, C and D types are largely classified into serine-beta-lactamase, and on the other hand, Class B type is classified into metallo-beta-lactamase. It has been known that both have respectively different mechanisms to each other in terms of hydrolysis of beta-lactam drugs.
Recently, clinical problem has been occurring due to the existence of Gram negative bacteria which have become highly resistant to beta-lactam drugs including Cephems and Carbapenems by production of Class A (ESBL) or D types serine-beta-lactamase and Class B type metallo-beta-lactamase which have extended their substrate spectrum. Particularly, metallo-beta-lactamase is known to be one of the causes of obtaining multi-resistancy in Gram negative bacteria. Cephem compounds which exhibit intermediate activity against metallo-beta-lactamase producing Gram negative bacteria are known (e.g., Patent Document 1 and Non-Patent Document 1). However, there is a demand for development of Cephem compounds which exhibit more potent antimicrobial activity, in particular effectivity against a variety of beta-lactamase producing Gram negative bacteria.
One of the known antimicrobials having high anti-Gram negative bactericidal activity is Cephem compounds having a catechol group intramolecularly (e.g., Non-Patent Documents 2-4). The action thereof is that the catechol group forms a chelate with Fe3+, thereby the compound 1s efficiently incorporated into the bacterial body by means of Fe3+ transportation system on the cellular membrane (tonB-dependent iron transport system). Therefore, research has been conducted on compounds having catechol or similar structure thereto, on the 3-side chain or 7-side chain on the Cephem backbone.
Patent Documents 2-8 and Non-patent Documents 2-11 and 16 disclose compounds having a catechol or a structure similar thereto on the 3-side chain of the Cephem backbone.
Patent Documents 9 and 12-14, and Non-patent Documents 12-15 disclose compounds having a catechol or a structure similar thereto on the 7-side chain of the Cephem backbone.
Non-patent Documents 7, 9, 10 and 12-15 describe Cephem compounds which have been stabilized against beta-lactamase.
However, these documents do not disclose the compounds of the subject invention. Furthermore, these documents, which describe Cephem compounds having catechol group intramolecularly, have no specific description regarding metallo-beta-lactamase of Class B type, or antibacterial activity against wide spectrum of Gram negative bacteria including Class B type.
Patent Documents 10 and 11 do not specifically disclose Cephem compounds having catechol type substituents. However, the present applicant filed an application of Cephem compounds having catechol type substituents (Patent Documents 12-14).